The present invention relates to indwelling or implanted medical devices treated with an antimicrobial agent to inhibit the growth of bacterial and fungal organisms. The invention also relates to a method of treating indwelling or implanted medical devices with an antimicrobial agent.
Indwelling medical devices such as catheters are becoming essential to patient care. The benefit derived from these catheters, orthopedic devices, and other types of medical implants, however, is often offset by infectious complications.
Some of the common organisms causing infectious complications associated with indwelling medical devices are Staphylococcus epidermidis and Staphylococcus aureus. In the case of vascular catheters, these two organisms account for almost 70-80% of all infectious organisms, with Staphylococcus epidermidis being the most common organism. Gram-negative bacilli cause about 15-20% of the infections, and Candida species, a fungal agent, accounts for about 10-15% of the vascular catheter infections. Other gram-negative bacteria and fungal organisms (Candida) account for the remaining one-third of cases.
Another common hospital-acquired infection is a urinary tract infection (UTI). The majority of UTI cases are associated with the use of urinary catheters, including transurethral foley, suprapubic and nephrostomy catheters. These urinary catheters are inserted in a variety of populations, including the elderly, stroke victims, spinal cord-injured patients, postoperative patients and those with obstructive uropathy. Despite adherence to sterile guidelines for the insertion and maintenance of urinary catheters, catheter-associated UTI continues to pose a major problem. In the U.S. alone, about 1 million cases of hospital-acquired cases of UTI occur annually. For instance, it is estimated that almost one-quarter of hospitalized spinal cord-injured patients develop symptomatic UTI during their hospital course. Gram-negative bacilli account for almost 60-70%, enterococci for about 25% and Canada species for about 10% of cases of UTI.
Colonization of bacteria on the surfaces of the implant or other parts of the device can produce serious patient problems, including the need to remove and/or replace the implanted device and to vigorously treat secondary infective conditions. A considerable amount of attention and study has been directed toward preventing such colonization by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. In such attempts, the objective has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization.
Various methods have previously been employed to prevent infection of medical devices. A simple method is to flush the surfaces of a device with an antimicrobial solution. Generally, this flushing technique requires convenient access to the implantable device. For example, catheters are generally amenable to flushing with a solution of rifampin and minocycline or rifampin and novobiocin. For use in flushing solutions, the effective concentration of the antibiotic range from about 1 to 10 mg/ml for minocycline, preferably about 2 mg/ml; 1 to 10 mg/ml for rifampin, preferably about 2 mg/ml; and 1 to 10 mg/ml for novobiocin, preferably about 2 mg/ml. The flushing solution is normally composed of sterile water or sterile saline solutions.
Other methods of coating surfaces of medical devices with antimicrobial agents are taught in U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pKa of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ironically bind antibiotics); U.S. Pat. No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); U.S. Pat. No. 4,95,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders); and U.S. Pat. No. 4,442,133.
These and other methods of coating medical devices with antimicrobial agents appear in numerous patents and medical journal articles. However, these methods also have significant drawbacks in that they can alter the integrity of non-metallic medical devices or result in residual antimicrobial material precipitating within the device.
Accordingly, there is a need for a non-metallic medical device treated with an antimicrobial agent to provide a broad range of antimicrobial activity while minimizing the harmful side effects noted above. Further, there is a need for a method that results in low residual coating material left on the surface of the medical device, which reduces complications arising from precipitation of coating material within the device. There is also a need to enhance the versatility of the treatment to accommodate higher concentrations of antimicrobial agents if needed.
One aspect of the present invention is a method for treating non-metallic medical devices with an antimicrobial agent comprising the steps of mixing at least an antimicrobial agent, an acid solution, and glycerol to form an antimicrobial composition and applying the antimicrobial composition to at least a portion of the non-metallic medical device under conditions wherein an effective concentration of the antimicrobial composition binds to the non-metallic medical device.
In a specific embodiment, the antimicrobial composition may be formed by mixing antimicrobial agents and an acid solution and then adding glycerol.
In another specific embodiment, the antimicrobial agent may be selected from the chlorhexidine and methylisothiazolone; chlorhexidine and xcex1-terpineol; thymol and chloroxylenol; thymol and methylisothiazolone; chlorhexidine and cetylpyridinium chloride; chlorhexidine and chloroxylenol; chlorhexidine, methylisothiazolone and thymol; methylisothiazolone and xcex1-terpineol; minocycline and rifampin; and chlorhexidine, methylisothiazolone and xcex1-terpineol.
In another specific embodiment, the portion of the non-metallic medical device treated may be made from rubber, plastic, nylon, silicone, polyurethane, polyethylene, polyvinyl chloride, polytetrafluoroethylene tetraphthalate, polyethylene tetraphthalate, polytetrafluoroethylene, latex, elastomers, polymers, and materials sealed with gelatin, collagen or alumin.
In another specific embodiment, the non-metallic medical device may be a peripherally insertable central venous catheter, dialysis catheter, long term tunneled central venous catheter, peripheral venous catheter, short-term central venous catheter, arterial catheter, pulmonary artery Swan-Ganz catheter, urinary catheter, long term non-tunneled central venous catheters, peritoneal catheters, ventricular catheters, long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, extravascular grafts, urinary stints, vascular catheter ports, wound drain tubes, hydrocephalus shunts, pacemaker systems, artificial urinary sphincters, vascular dialators, extravascular dialators, vascular stints, extravascular stints, small joint replacements, temporary joint replacements, urinary dilators, heart valves, orthopedic implants, heart assist devices, stents, penial implants mammary implants, and dental devices.
In another specific embodiment, the acid solution may be a short chain monocarboxylic acid and ortho-phosphoric acid. The short chain monocarboxylic acid may be formic acid, acetic acid, or propionic acid.
A further specific embodiment includes the ratio of monocarboxylic acid to ortho-phosphoric acid to glycerol may be about 79:8:13.
In another specific embodiment, the antimicrobial composition has a temperature that is between 2xc2x0 C. to 75xc2x0 C. at some point during the treatment, preferably about 45xc2x0 C.
In another specific embodiment, the acid solution may also contain potassium chloride.
In another specific embodiment, the antimicrobial composition may be applied by exposing the non-metallic medical device to the antimicrobial composition for about 10 minutes to about 18 hours, preferably about 60 minutes.
In another specific embodiment, the method of treating the non-metallic miedical-device may further comprise the step of removing excess antimicrobial composition from the non-metallic medical device after the application step and then drying the non-metallic medical device. The non-metallic medical device may be dried for about 16 hour
In another specific embodiment, the non-metallic medical device may be flushed with water after the drying step and may then be dried again for about 10 hours to about 24 hours.
A further embodiment of the invention provides for an implantable medical device comprising a body; one or more non-metallic surfaces on said body, glycerol, and an antimicrobial agent, wherein the glycerol and an effective concentration of the antimicrobial agent coat the one or more non-metallic surfaces.
In another specific embodiment, the antimicrobial agent may be selected from the group consisting of chlorhexidine and methylisothiazolone; chlorhexidine and xcex1-terpineol; thymol and chloroxylenol; thymol and methylisothiazolone; chlorhexidine and cetylpyridinium chloride; chlorhexidine and chloroxylenol; chlorhexidine, methylisothiazolone and thymol; methylisothiazolone and xcex1-terpineol; minocycline and rifampin; and chlorhexidine, methylisothiazolone and xcex1-terpineol.
In another specific embodiment, the device may consist, at least in part, of rubber, plastic, silicone, polyurethane, polyethylene, polytetrafluoroethylene and polyethylene tetraphthalate and polyethylene tetraphthalate sealed with gelatin, collagen or albumin.
In another specific embodiment, the non-metallic medical device may be a peripherally insertable central venous catheter, dialysis catheter, long term tunneled central venous catheter, peripheral venous catheter, short-term central venous catheter, arterial catheter, pulmonary artery Swan-Ganz catheter, urinary catheter, long term non-tunneled central venous catheters, peritoneal catheters, ventricular catheters, long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, extravascular grafts, urinary stints, vascular catheter ports, wound drain tubes, hydrocephalus shunts, pacemaker systems, artificial urinary sphincters, vascular dialators, extravascular dialators, vascular stints, extravascular stints, small joint replacements, temporary joint replacements, urinary dilators, heart valves, orthopedic implants, heart assist devices, stents, penial implants, mammary implants, and dental devices.
It is readily apparent to one skilled in the art that various embodiments and modifications may be made to the invention disclosed in this application without departing from the scope and spirit of the invention.
As used in the specification, xe2x80x9caxe2x80x9d or xe2x80x9canxe2x80x9d means one or more. As used in the claims (s), when used in conjunction with the word xe2x80x9ccomprising,xe2x80x9d the words xe2x80x9caxe2x80x9d or xe2x80x9canxe2x80x9d mean more or more. As used herein, xe2x80x9canotherxe2x80x9d means at least a second or more.
The term xe2x80x9cantimicrobial agentxe2x80x9d as used in the present invention means any single or combination of antiseptics, antibiotics, disinfectants, and antimicrobial peptides. Some examples antimicrobial agents include, but are not limited to, methylisothiazolone, thymol, xcex1-terpineol, cetylpyridinium chloride, chloroxylenol, hexachlorophene, chlorhekidine and other cationic biguanides, methylene chloride, iodine and iodophores, triclosan, taurinamides, nitrofurantoin, methenamine, aldehydes, azylic acid, silver, benzyl peroxide, alcohols, carboxylic acids, salts, erythromycin, nafcillin, cefazolin, imipenem, astreonam, gentamicin, sulfamethoxazole, vancomycin, ciprofloxacin, trimethoprim, rifampin, metronidazole, clindamycin, teicoplanin, mupirocin, azithromycin, clarithromycin, ofoxacin, lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, gatifloxacin, moxifloxacin, gemifloxacin, enoxacin, fleroxacin, minocycline, linexolid, temafloxacin, tosufloxacin, clinafloxacin, sulbactam, clavulanic acid, amphotericin B, fluconazole, itraconazole, ketoconazole, nystatin, penicilins, cephlalosporins, carbepenems, beta-lactams antibiotics, aminoglycosides, macrolides, lincosamides glycopeeptides, tetracylines, chloramphenicol, quinolones, fucidines, sulfonamides, trimethoprims, rifamycins, oxalines, streptogramins, lipepeptides, ketolides, polyenes, azoles, and echinocandines. Other examples of antibiotics, such as those listed in Sakamoto et al, U.S. Pat. No. 4,642,104 herein incorporated by reference will readily suggest themselves to those of ordinary skill in the art.
These antimicrobial agents preferably used in combinations of two or more to obtain a synergistic effect. They are dispersed along the surface of the medical device to provide a broad range of antimicrobial activity.
Some examples include chlorhexidine and methylisothiazolone; chlorhexidine and xcex1-terpineol; thymol and chloroxylenol; thymol and methylisothiazolone; chlorhexidine and cetylpyridinium chloride; chlorhexidine and chloroxylenol; chlorhexidine, methylisothiazolone and thymol; methylisothiazolone and xcex1-terpineol; minocycline and rifampin; and chlorhexidine, methylisothiazolone and xcex1-terpineol. These combinations provide a broad spectrum of activity against a wide variety of organisms.
The amount of antimicrobial agent used to treat a medical device varies to some extent, but is at least a sufficient amount to form an effective concentration to inhibit the growth of bacterial and fungal organisms, such as staphylococci, gram-positive bacteria, gram-negative bacilli and Candida.
The term xe2x80x9ceffective concentrationxe2x80x9d means a sufficient amount of an antimicrobial agent to decrease, prevent or inhibit the growth of bacterial and/or fungal organisms. The amount will vary for each compound and upon known factors such as pharmaceutical characteristics; the type of medical device; age, sex, health and weight of the recipient, and the use and length of use. It is within the skilled artisan""s ability to relatively easily determine an effective concentration of an antimicrobial agent for different antimicrobial agents and different known factors.
The antimicrobial agents may antiseptics. The use of antiseptics may provide more efficacy against gram-negative bacteria and Candida species than antibiotic combinations. Although the different mixtures of antiseptics can be used for all medical devices, certain mixtures work better with different devices. Different combinations of antiseptics can be used for different types of medical devices depending on the spectrum of organisms that cause the infections related to each device. For instance, preferred combinations of treating orthopedic devices include chlorhexidine, methylisothiazolone and xcex1-terpineol; chlorhexidine and cetylpyridinium chloride; chlorhexidine and chloroxylenol; or chlorhexidine, methylisothiazolone and thymol. The combination of different antiseptics has a synergistic effect against certain bacteria and fungi.
The term xe2x80x9cbacterial and fungal organismsxe2x80x9d as used in the present invention means all genera and species of bacteria and fungi, including but not limited to all spherical, rod-shaped and spiral organisms. One skilled inthe art recognizes that a variety of source books which list and describe bacteria and fungi are available, for example in the textbook xe2x80x9cPrinciples and Practice of Infectious Diseisesxe2x80x9d, Mandell et al., 4th edition, 1995, Churchill Livingstone, N.Y. Some examples of bacteria are staphylococci (i.e. Staphylococcus epidermidis, Staphylococcus aureus), Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, other gram-positve bactera and gram-negative bacilli. One example of a fungus is Candida albicans: 
The term xe2x80x9cglycerolxe2x80x9d means glycerol or glyceride.
As used herein xe2x80x9cimplantedxe2x80x9d devices includes both temporary and permanent devices and indwelling and implanted devices.
The medical devices which are amenable to treatment according to one aspect of the present invention are non-metallic. However, non-metallic portions or components of metallic devices may be treated. Treatable medical devices may also include devices that are formed from more than one type of non-metallic material.
Non-metallic materials that can be treated by the method of the present invention include, but are not limited to, rubber, plastic, nylon, silicone, polyurethane, polyethylene, polyvinyl chloride, Gortex (polytetrafluoroethylene tetraphthalate), Dacron (polyethylene tetraphthalate), Teflon (polytetrafluoroethylene), latex, elastomers, polymers, and materials sealed with gelatin, collagen or albumin.
Particular non-metallic medical devices suited for the antimicrobial treatment of the present invention include, but are not limited to, peripherally insertable central venous catheters, dialysis catheters, long term tunneled central venous catheters, long term non-tunneled central venous catheters, peripheral venous catheters, short-term central venous catheters, arterial catheters, pulmonary arty Swan-Ganz catheters, urinary catheters, long term urinary devices, tissue bonding urinary devices, penile prostheses, vascular grafts, extravascular grafts, urinary stints, vascular catheter ports, wound drain tubes, hydrocephalus shunts, peritoneal catheters, pacemaker systems, artificial urinary sphincters, vascular dialators, extravascular dialators, vascular stints, extravascular stints, ventricular catheters, small joint replacements, temporary -joint replacements, urinary dilators, heart valves, orthopedic implants, heart assist devices, stents, penial implants, mammary implants, dental devices, and the like.
In addition to treating non-metallic medical devices, the present invention may also be used to treat miscellaneous surfaces, such as hospital floors, nursing counters, counters adjacent to washing basins, desks, etc. to decrease transmission of hospital antibiotic-resistant microbial flora, such as methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococci and antibiotic-resistant gram negative bacteria on the skin of health care personnel and patients. Another potential application is the treatment of kitchen counters to decrease transmission of organisms that cause food-borne poisoning, such as Salmonella species and Escherichia coli. 
The non-metallic medical device may be treated with an antimicrobial composition by applying a sufficient amount of the antimicrobial composition to at least a portion of the medical device under conditions wherein at least a portion of the antimicrobial composition binds with the non-metallic portions of the medical device. Although it is contemplated that the antimicrobial agents will bind with the medical device, other ingredients such as anti coagulants and anti-inflammatory agents may be included in the antimicrobial composition and may also bind with the medical device. It is also contemplated that a non-metallic medical device may be treated with a composition of non-antimicrobial agents.
The following examples are offered by way of illustration and are not intended to limit the invention in any manner.